Glycyrrhetinic acid derivatives



April 2, 1963 s. GOTTFRIED a-rm. 3,084,185

GLYCYRRHETINIC ACID DERIVATIVES Filed July 21, 1960 2 Sheets-Sheet 1 i O :m

April 1963 s. GOTIFRIED EI'AL 3,084,185

GLYCYRRHETINIC ACID DERIVATIVES Filed July 21, 1960 2 Sheets-Sheet 2 after referred to as the war-compounds and the cispounds are 3,084,185 Patented Apr. 2, 1963 The present invention is concerned with new and therapeutically useful derivatives of glycyrrhetinic acid.

It is known from copending application, Ser. No. 645,898, filed March 14, 1957, and now abandoned, that glycyrrhetinic acid either alone or in combination with one or more anti-causative substances is a useful therapeutic agent not only for the treatment of inflammatory conditions but also for the trearnent of a large variety of skin diseases and pruriginous skin conditions.

Various esters and hen1i-esters of glycyrrhetinic acid are mentioned in copending application Serial No. 744,133, filed June 26, 1958, and now US. Patent 2,915,825, and, in addition, various other therapeutically useful derivatives of giycyrrhetinic acid are mentioned in copending applications, Serial No. 742,706, filed June 18, 1958, and Serial No. 771,182, filed November 3, 1958.

We have now found that when glycyrrhetinic acid is chemically treated in such a manner that double bonds are introduced therein or that halogen atoms or ethinyl groups are introduced therein, a potentiation of activity takes place. Such glycyrrhetinic acid derivatives have the same field of therapeutic application as the glycyrrhetinic acid derivatives described and claimed in the aforesaid copending applications, Serial Nos. 744,688; 742,706; and 771,182.

Thus, according to the present invention, there are provided glycyrrhetinic acid derivatives of the general forrnuia:

wherein A, B, C and D are hydrogen atoms or A and B and/or C and D can together represent a further bond and X is a hydroxyl, ethinyl r acyl-oxymethyl CH .O.acyl) radical.

It should also be explained that the two rings Y and Z in the above-given general formula may be joined in the cis-or trans-position. .The trans-compounds are hereincomreferred to as the lSfl-compounds.

3,1l-diketo-18orand 1Sfi-olean-12-en-20-carboxylic acids, herein referred to as 180:- and 18,8-keto G.A. respec- :tively, have already been prepared by Logemann et al. (Ber. 90, 603/ 195 7) from 3-hydroxy-1l-keto-lSfl-olean- 2 l2-en-20-carboxylic acid (i.e., glycyrrhetinic acid). However, the method used by Logernann et al. does not give very high yields and according to a further feature of the present invention processes are provided for the production of l8ozand l8p-keto G.A. which give high yields of high purity.

18% and 18,3-keto G.A. can be monohalogenated in the usual manner, such as by dissolving 185 keto G.A. in an inert organic solvent and adding one molecular equivalent of halogen. In this case halogenation takes place at the 2-position.

The tri-halogen derivative can manner, i.e., by treating the 18mand 18,8-keto G.A. in an inert organic solvent with 2 molecular equivalents of halogen and, in this case, not only is a halogen atom substituted in the 2-position but two halogen atoms are also added across the 12,13-double bond. This tri-halogen derivative is also new. It will be understood, however, that in the case of the trihalogenation of l8ozand 18,8-keto G.A., the same compound is obtained.

These halogen derivatives can be dehydrohalogenated in a known manner, for example, by treatment with a basic reagent, such as pyridine. In the case of the dehydrohalogenation of the mono-halo compounds, a double bond is formed in the 1,2-position. Thus, the mono-halo-lSoaketo G.A. and the mono-halo-lSfi keto G.A. give rise to A -18u-lceto G.A. and A -18 -keto G.A., respectively.

When the trihalo derivatives are dehydrohalogenated, not only is a double bond formed in the 1,2-position but the double bond in the 12,13-position is reformed and a further double bond is formed in the 18,19-position. Thus, the trihalo-l-S/i-keto G.A. gives rise to A -keto G.A.

be prepared in a similar The ZO-carboxylic acid group in N-ISB-keto G.A. and in A -18a-G.A., as well as in 18x-keto G.A. and ISp-keto G.A., may be converted into the corresponding acid chloride group by reaction with, for example, thionyl chloride or, better oxalyl chloride, preferably at elevated temperatures. The resulting 20 -acid chlorides are valuable intermediates in the preparation of further derivatives, particularly for the preparation of the corresponding ethinyl derivatives.

These ethinyl derivatives are prepared in a known manner by the reaction of the 20-acid chloride with, for example, sodium acetylide in an inert solvent, such as benzene.

The acyloxy-methyl compounds may be prepared from the ZO-acid chloride, by reacting the acid chloride with the reaction scheme.

The following Examples 7, 8, l0 and 11 are given for the purpose of illustrating the present invention and Examples 1-6 and 9 for the purpose of illustrating the preparation of intermediates, the Roman numerals referring to the structural formulae in the accompanying drawings:

Example 1 .Preparation of 3,11 -D iket0-18,8-O lean JZ-En-ZO-Carboxylic Acid -(]8fl-Ket0 GA (I) 23.5 g. l8fi-glycyrrhetinic acid are dissolved in a mixture of cc. glacial acetic acid and 100 cc. alcoholfree chloroform and 5 g. chromic anhydride dissolved in 25 cc. glacial acetic acid and cc. water carefully mixed therewith. The temperature of the reaction mixture is not allowed to rise above 30 C. After a period of three hours, cc. methanol are added, the mixture reduced to a small volume by evaporation under reduced pressure, 4 times the volume of water is added thereto, the precipitate obtained is dried and then dissolved in a solution of 7 5 cc. 2 N sodium hydroxide in 100 cc. water and 100 cc. industrial methylated spirit, boiled and filtered. (The technique of boiling to alkaline solution of the product, after removal of acetate ions, results in the decomposition of soluble chromium compounds, which otherwise impair the subsequentcrystallisation, to give the insoluble chromic oxide which iscompletely removed by filtration.) After acidification of the solution obtained, 2.05 g. crude 18 6- keto G.A. (I) are obtained. This crude compound-is dissolved in a mixture of 200 cc. methanol and 125 cc. chlorotorm evaporateddown a little, if necessary, and allowed to crystallise in an ice chest (M.P. 295 C.).

As stated above, the method of preparing 18ri-keto G.A. according to the present invention issuperior to that described'by Logemann et al. in that the yield is higher and the product obtained is considerably purer, i.e., in this example the yield of pure product was 19 'g. (8081% yield) whereas Logemanns yield was 70-71%.

Example 2.Preparation of 3,11-Diketo-18fl-0lean-12- En-ZO-Carboxylz'c Acid (18 8-Ket0-GA.) (I) A solution of 5 g. chromic anhydride in 5 cc. water and 25 cc. glacial acetic acid is added slowly to a .cold stirred solution of 23.5 g. 18,6-G.A. in 250 cc. glacial acetic acid. The temperature of the reaction mixture is not allowed to rise above 2530 C. After standing for about 12 hours, the mixture is heated on the steam bath to about 80 C.

for -15 minutes and 10 cc. methanol then added. The

mixture is poured into about one litre water, the precipirated filtered off with suction, dried first at 100 C. and then in vacuo over potassium hydroxide. This ensures that all the acetic acid is removed. A powdery green solid is obtained.

The precipitate is then mixed with 200 cc. methylated spirit, 100 cc. water and 50 cc. 2 N aqueous sodium hydroxide and the suspension obtained digested on a steam bath for 30 minutes. This process brings all the 183- keto-A.G. into solution and precipitates all the chromium as chromium hydroxide (Cr(OH The hot alkaline solution is filtered and the filtrate poured into 1 litre water containing 100 cc. 2 N aqueous hydrochloric acid. A white precipitate of crude ISfi-keto-GA. is immediately thrown down. This precipitate is filtered off with suction and dried. The dry crude product amounts to 21 g. It is purified by dissolving in a mixture of 200 cc. methanol and '125 cc. chloroform, evaporating the solution down, if

necessary, and allowing to crystallise. Repeated recrystallisation and working up of the mother liquors gives 19 g. (81% of theory) .pure IS-fi-lreto-GA. in the "form of colourless rhomboidal crystals or M.P. 295 C.; {113 =+184 in chloroform (C=l).

Example 3. Preparalion of 3,11-Diketo-18a-0lean-I2- En-ZO-Carboxylic Acid ,(180C-K6t0-G-A.) (IX) 53 g. l8a-G.A. is suspended in 1500 cc. glacial acetic acid in a round-bottomed flask. A soxhlet extractor containing 8.0 g. chromic anhydride in a Gooch crucible is placed in the neck of the flask and the glacial acid mixture boiled under reflux at reduced pressure, the temperature not being allowed to rise above 40 C. Aiter 8 hours, the mixture is poured into 5 litres water and the resulting suspension filtered. The precipitate is dried at 100 C. and'then in vacuo over potassium hydroxide.

The solid product is then digested on the steam bath for 30 minutes in a mixture of 75 cc. 2 N aqueous sodium hydroxide, 100 cc. water and 200 cc. methylated spirit. The alkaline mixture is filtered and poured into '2 litres water containing 100 cc. 2 N aqueous hydrochloric acid.

The precipitate was filtered oii with suction and dried at C. 50 g. crude 18a-keto-G.A. are obtained. Recrystallisation from glacial acetic acid and working up of the mother liquors gives about 30 g. pure 18u-keto-G.A. of M.P. 328-9 C.; [a] =+125 in chloroform (C=0.8).

Example 4.-Preparation of 3,1 1-Diketo-18a-0lean-12- En-ZO-Carboxylic Acid .(18a-Ket0-GA.) (IX) Example 5.Preparati0n of 2- -Br0m0-3 ,11-Dikei0-18B- Olean-IZ-Ene-ZO-Carboxylic Acid (Monobramo-ltifi- Keto G.A.) (V) 20 cc. of a molar solution of bromine in acetic acid is slowly added to 9.4 g. 18fi-keto GA. in 300 cc. glacial acetic acid at room temperature. The mixture is allowed to stand for 30 minutes and 500 cc. cold water then added slowly. The resulting precipitate is filtered oil and dried in vacuo at room temperature. 10.5 .g. crude monobromo-18;S-keto-G.A. are obtained. The crude material is purified by dissolving in cold acetone, adding methanol and allowing the solution to evaporate at room temperature. Recrystallisation gives colourless needles of M.P. 240 C.; [u] =+180 in chloroform (C=0.2).

Analysis.-C H 0 Br. Calculated 0:65.80; H: 7.92; Br=14.59. Found C=66.30; H=8.01; Br=15.25. The solid decomposes on standing and turns pale brown.

In the same manner, 2-brorno3,11-dikto-18m-olean-12- en-20carboxylic acid (monobromo-18a-keto G.A. .(X'I) may be prepared from lSu-keto G.A.) (1X).

Example 6.-Preparazion of 2,12,13-Tribr0m0-3,11-Diketo-18u-0lean 20 Carboxylic Acid (Tribromo-18B- G.A.) (II solution to evaporate. Colourless needles are obtained at M.P. 255-6 C. The substance slowly decomposes on standing.

Analysis.C I-I O Br Calculated Br=33.89%. Found Br=32.08%. In this tribromo compound, bromine is substituted in the 2-position and also added to the 12- and Iii-positions, the 12,13 double bond being thereby eliminated.

18u-keto G.A. (IX) may be tribrominated in the same manner and, in this case, the product will be the same as that obtained by the tribromination of 18fi-keto G.A. i.e. compound II. When -tribromo-18B-keto G.A. isrecrystallised .from a solvent, such as glacial acetic acid or methanol, dehydrobromination apparently takes place at the 12,13 and 18,19 positions to give 2-bromo-3,11-dikctoclean-12,l8adiene-20-carboxylic acid, i.e. monobromo-A keto-G.A. This substance crystallises from acetic acid as colourless plates of M.P. 272-274 C.

Analysis-Bromine (found) 14.55%; (calc.) 14.66%.

Example 7.-Preparation of 3,11-Diket0-18fl-0lean-LI2- Dien-ZO-Carboxylic Acid (A -18 3-Keto G.A.) (V1) 11.0 g. pure monobromo-lSfi-keto-GA. are mixed with 75 cc. dimethyl formamide and 25 cc. quinaldine and the golden solution obtained boiled in an atmosphere of in the presence of benzene.

nitrogen for 4 hours. The dark green reaction mixture is poured into a mixture of 20 cc. concentrated hydrochloric acid and 200 cc. water and the resulting precipitate filtered 01f, washed thoroughly with water and dried on a steam bath. The crude material thus obtained is crystallised by dissolving in a mixture of acetone and benzene and evaporating to low bulk. Pure A -18B-keto-GA. of MP. 291-2" C. crystallises in the form of colourless rhomboids; [a] =j-233 in chloroform B.P. (0:2); a =4.68 (i0.0l) (2 dm.).

Analysis.-C H O Calc.: C 77.21; H 9.07. Found: C 77.20; H 9.14.

Using the same method, monobromo-l8a-keto-GA. gives A -18a-keto-GA. in the form of colourless plates of MP. 333-4 'C., [a] =+146 in chloroform (C=1.6): q =+2.41 (i0.0 l) (2 dm.).

Example 8.Preparati0n 0f 3,11-Diket0-Olean-I,]2,]8- Trien-20-Carboxylic Acid (A -Keto-GA.) (III) 12 g. tn'bromo-18B-keto G.A., which may be prepared as described in Example 6, is mixed with 75 cc. dimethyl formamide and 25 cc. quinaldine and the golden solution obtained boiled in an atmosphere of nitrogen for 4 hours. The crude green mixture obtained is poured into a mixture of 20 cc. concentrated hydrochloric acid and 200 cc. Water and the resulting precipitate filtered off, washed thoroughly with water and dried on a steam bath. The crude material is recrystallised by dissolving in methanolic chloroform and evaporating to a small bulk; MP. 306-7 C. The same product is obtained if, instead of A -keto-GA. there is used 11 g. monobromo-A -keto- G.A.

Example 9.Preparati0n of 3,1J-Diket0-I8/3-0lean-1,12- Dien-ZO-Carboxylic Acid Chloride (A 18,8-Ket0 G.A. Chloride) (VIa) Example J0.Preparation of 3,1J-Dikeio-20-Ethinyl- Carbonyl-lfi-Olean 1,12-Diene(Ethinylket0-A -18fl- Keto G.A.) (VII) The acid chloride of N-lSfi-keto G.A., which may be prepared in the manner described in Example 9, is caused to react with one molecular equivalent of sodium acetylide In this manner, the acid chlo'. ride group is converted into an ethinyl keto group giving rise to ethinyl keto A -18fi-keto GA. (VII).

In the same manner, 3,1l-diketo-ZO-(ethinyl-carbonyl)- clean-1,12,18-triene(ethinylketo A1118 keto G.A. (IV) may be prepared from the acid chloride of A -keto- G.A.-(IIIa), 3,1l-diketo-20-(ethinyl-carbonyl) ISB-olean- 12-ene (ethinylketo-ltlp-keto G.A.) (VIII) from the acid chloride of 18 6-keto G.A. ('Ia), 3,11-diketo-20-(ethinylcarbonyl) -18a-olean-12-ene(ethinylketo-18a-keto (G.A.) (X) from the acid chloride of ISa-keto G.A. (IXa) and 3,1l-diketo-20-(ethinyl-carbonyl)-18u-olean 1,12 diene (ethinyl-keto-d -l8u-keto G.A.) (XIII) from the acid chloride of A -18a-keto G.A. (XI-Ia).

Example 1] .Preparation 0 f 3,11-Diket0-20- (w-Acetoxy- A cetyl) -Olean-] ,12,I 8-Triene(A cetoacety l-A Kezo GA (XIV) The ZO-acid chloride A -keto G.A. (Ilia), which may be prepared in the manner described in Example 9, is caused to react with diazomethane to give the corresponding diazoketone which, in turn, is caused to react with acetic acid in the presence of potassium acetate. In this manner, the 20-acid chloride is converted into the corrediene.

,jecting the corresponding the latter to the action spending acetoxy acetyl derivative (XIV). In the same manner, 3,1 l-diketo-ZO- (w-acetoxyacetyl) -1 8,8-olean-1, 12- diene (acetoacetyl-A -l8 3-keto G.A.) (XV) may be prepared from the acid chloride of A -l8/3-keto G.A. (V161) and 3,1l-diketo-ZO-(w-acetoxyacetyl) -18a-olean1,12-diene (acetoacetyl-A -18a-keto G.A.) (XVI) from the acid chloride of A -18a-keto G.A.

It is to be understood that all the new derivatives of :glycyrrhetinic acid which come with-in the scope of the present invention may be solubilised by known methods. Of special utility 'for this purpose there may be mentioned Girards Reagent T (H 'NNH.CO.CH N+(CH .(C1-) However, similar hydrazine ammonium compounds may also be used. Furthermore, in addition to the new compounds within the purview of the present application, it is also possible to solubilise in this manner, 3, ll-diketo- 20-(m-acetoxy-acetyl)-l8aand 18;3-olean-l2-ene, these two compounds having already been described by Logemann et al. (v. supra).

What we claim is: i

l. 3,1l-diketo-l8 8-olean-1,12-dien-20-carboxylic acid.

2. 3,1l-diketo-l8a-olean-1, 12-dien-20-carboxylic acid.

3. 3,11-diketo-olean-1,12,18-trien-20-carboxylic acid.

4. 3,11-diketo-2O-(ethinyl carbonyl)-18a-olean-1,12- diene.

5. 3,11-diketo-20-(ethinyl carbonyl) clean-1,12,18- triene.

6. 3,11-diketo-20-(ethinyl carbonyD-lSfi olean-12- 9. 3,1l-diketo-20-(w-acetoxy acetyl) -o1ean-1,12,18-triene. v v

10. 3,11,diketo-2Q.-(w acetoxyacetyl) 18fl-olean-1,12- diene.

l1. 3,11-diketor20-(oracetoxyacetyl) 18a-olean -1, l 2

12. A process for the preparation of a 3,11-diketo-18ctclean-1,l2-dien-20-carboxylic acid, which comprises sub- 3,1Ldiketo-l8ot-olean-12-en20- carboxylic acid to the action of bromine until one bromine atom has added on, thereby yielding the corresponding 2-bromo compound, and subjecting the latter to the action of a dehydrobrominating agent, whereby the corresponding 1,-12-diene is produced.

13. A process [for theprep'aration of a 3,11-diketol-SB-olean-l,IZ-dieh-ZO-Carboxylic acid, which comprises subjecting the corresponding 3,1l-diketo-lSfl-olean-lZ-en- ZO-canboxylic acid to the action of bromine until one bromine atom has added on, thereby yielding the corresponding 2-bromo compound, and subjecting the latter to the action of a dehydrobrominating agent, whereby the corresponding 1,12-diene is produced.

14. A process for the preparation of a 3,11-diketo18- clean-1,12,18-triene-20-carboxylic acid, which comprises subjecting the corresponding 3,1l-diketo-l8a-olean-12-en- ZO-carboxylic acid to the action of bromine until three bromine atoms have added on, thereby yielding the corresponding 2,l2,l3-tribromo compound, and subjecting of a dehydrobrominating agent, whereby the corresponding 1,12,18-triene is produced.

15. A process for the preparation of a 3,1l-diketo-18- olean-l,12,1S-triene-Z-O-carboxylic acid, which comprises subjecting the corresponding 3,1l-diketo-lSB-olean-l2-en- 20-carboxylic acid to the action of bromine until three bromine atoms have added on, thereby yielding the corresponding 2,12,13-tribromo compound, and subjecting the latter to the action of a dehydrobrominating agent, whereby the corresponding 1,12,18-triene is produced.

1 1- 6. A processifor thepreparation of a compound of the formula is a member selected from the group consisting of and i the :moiety is a member selected :from the group consisting of p and and the rings Y and .Z being in one of the relationships cis and trans with respect to each other, which comprises suhiecting the corresponding ZO-COOH compound to the action of a chlorina'ting agent, whereby the corresponding acid chloride results, and subjecting the said acid chloride to the action of an ethinyla'ting agent, whereby the desired ethinyl-substituted compound is obtained.

17. A process according to claim 16, wherein the chlorinating agent is selected from the group consisting of thionyl chloride and oxalyl chloride.

18. A process according to claim 17, wherein the ethiny'iating agent 'is sodium 'acetylide.

19. A process according to claim 16, wherein the ethinylating agent is sodium acetylide.

s8 20. .A process for the preparation of a compound of the formula O O -acy'loxymethyl wherein the moiety is a member selected from the group consisting of H and the moiety is a member selected from the group consisting of and the rings Y and Z being in one of the relationships cis and trans with respect to each other, which comprises subjecting-the corresponding 20-acid chloride to the action of diazome'thane, and then reacting the resultant diaz0- ketone with the corresponding carboxylic acid.

21. A process according to claim 20, wherein the carboxylic acid is acetic acid.

References Cited in the file of this patent Wagner et aL: Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York (1953), page 80.

'Logermann et a1.: Chemische Berichte, 90, 601-4 (1957).

iFieser et aL: Steroids, Reinhold Publishing Corp, New York (1959), pages .280 to 294, 557 and 623. 

20. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA 1-D,2,4A,6A,6B,9,9,12A-HEPTA(H3C-),2-(ACRYLOXYMETHYL-CO-), 10,13-DI(O=),11-A,12-B,14B-C-14,14A-DIDEHYDROPICENE 